c-Jun/p38MAPK/ASIC3 pathways specifically activated by nerve growth factor through TrkA are crucial for mechanical allodynia development

Chaumette, Tanguy; Delay, Lauriane; Barbier, J.; Boudieu, Ludivine; Aissouni, Youssef; Méleine, Mathieu; Lashermes, Amandine; Legha, Wassim; Antraigue, Sophie; Carvalho, Frédéric A.; Eschalier, Alain; Ardid, Denis; Moqrich, Aziz; Marchand, Fabien

doi:10.1097/j.pain.0000000000001808

Cited by 20 publications

(21 citation statements)

References 55 publications

(71 reference statements)

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“…Further mechanistic study revealed that NGF upregulated the expression of ASIC3 through c-jun/p38MAPK pathway and that ASIC3 was crucial for the development of NGF-induced mechanical hyperalgesia. 37 Consistent with their studies, we found that ASIC3 agonist recapitulated tooth mechanical hyperalgesia that was attenuated by periodontal administration of anti-NGF neutralizing antibody. Moreover, our results revealed that ASIC3 antagonist could attenuate tooth mechanical hyperalgesia that was aggravated by periodontal administration of NGF.…”

Section: Discussionsupporting

confidence: 91%

Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

Gao

Yan

et al. 2021

Int J Oral Sci

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Orthodontic tooth movement elicits alveolar bone remodeling and orofacial pain that is manifested by tooth mechanical hyperalgesia. Nerve growth factor (NGF) is upregulated in periodontium and may modulate tooth mechanical hyperalgesia. The objectives were to examine the role of NGF in tooth mechanical hyperalgesia and to elucidate the underlying mechanisms. Tooth mechanical hyperalgesia was induced by ligating closed coil springs between incisors and molars in Sprague–Dawley rats. Retrograde labeling was performed by periodontal administration of fluor-conjugated NGF and the detection of fluorescence in trigeminal ganglia (TG). Lentivirus vectors carrying NGF shRNA were employed to knockdown the expression of NGF in TG. The administration of agonists, antagonists, and virus vectors into TG and periodontium was conducted. Tooth mechanical hyperalgesia was examined through the threshold of biting withdrawal. Our results revealed that tooth movement elicited tooth mechanical hyperalgesia that could be alleviated by NGF neutralizing antibody and that NGF was upregulated in periodontium (mainly in periodontal fibroblasts) and TG. Retrograde labeling revealed that periodontal NGF was retrogradely transported to TG after day 1. Acid-sensing ion channel 3 (ASIC3) and NGF were co-expressed in trigeminal neurons and the percentage of co-expression was significantly higher following tooth movement. The administration of NGF and NGF neutralizing antibody into TG could upregulate and downregulate the expression of ASIC3 in TG, respectively. NGF aggravated tooth mechanical hyperalgesia that could be alleviated by ASIC3 antagonist (APETx2). Moreover, NGF neutralizing antibody mitigated tooth mechanical hyperalgesia that could be recapitulated by ASIC3 agonist (GMQ). NGF-based gene therapy abolished tooth mechanical hyperalgesia and downregulated ASIC3 expression. Taken together, in response to force stimuli, periodontal fibroblasts upregulated the expressions of NGF that was retrogradely transported to TG, where NGF elicited tooth mechanical hyperalgesia through upregulating ASIC3. NGF-based gene therapy is a viable method in alleviating tooth-movement-induced mechanical hyperalgesia.

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Section: Discussionsupporting

confidence: 91%

Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

Gao

Yan

et al. 2021

Int J Oral Sci

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“… 5 , 25 , 60 Recent hypothesis-driven studies investigated mRNA levels in the skin, DRG, and spinal dorsal horn after incision in rodents and discovered multiple mediators to be regulated. 13 , 48 , 57 , 65 However, transcript levels correlate only up to 50% with factual levels of corresponding proteins, which renders the interpretation of RNA-based results and identification of novel targets are challenging. 44 Hence, a thorough understanding of incision-induced dynamics warrants the inclusion of comprehensive studies at the proteome level.…”

Section: Introductionmentioning

confidence: 99%

A proteome signature for acute incisional pain in dorsal root ganglia of mice

Pogatzki-Zahn

Gómez-Varela

Erdmann³

et al. 2021

Pain

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“…Several pain-related signaling pathway targeting ASICs have been previously characterized, including PKC (Baron et al, 2002), PKA (Leonard et al, 2003) or phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) (Duan et al, 2012). A MAPK-dependent transcriptional regulation of ASIC3 has been involved in the effect of NGF (Mamet et al, 2003; Chaumette et al, 2020) or interleukin 1β (Ross et al, 2016), and a MAPK-dependent transcriptional regulation of ASIC1a has also been associated to the effect of interleukin 6 (Zhou et al, 2015) or oxidative stress (Wu et al, 2020), but a MAPK-dependent phosphorylation of ASIC channels has never been described so far. Our data are consistent with a phosphorylation by JNK of the ASIC1b and ASIC3 (except mouse ASIC3) subunits.…”

Section: Discussionmentioning

confidence: 99%

C-Jun N-terminal kinase post-translational regulation of pain-related Acid-Sensing Ion Channels 1b and 3

Verkest

Diochot

Lingueglia

et al. 2021

Preprint

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Neuronal proton-gated Acid-Sensing Ion Channels (ASICs) participate in the detection of tissue acidosis, a phenomenon often encountered in painful pathological diseases. Such conditions often involve in parallel the activation of various signaling pathways such as the Mitogen Activated Protein Kinases (MAPKs) that ultimately leads to phenotype modifications of sensory neurons. Here, we identify one member of the MAPKs, c-Jun N-terminal Kinase (JNK), as a new post-translational positive regulator of ASIC channels in rodent sensory neurons. Recombinant H+-induced ASIC currents in HEK293 cells are potently inhibited within minutes by the JNK inhibitor SP600125 in a subunit and species dependent manner, targeting both rat and human ASIC1b and ASIC3 subunits but only mouse ASIC1b subunit. The regulation by JNK of recombinant ASIC1b- and ASIC3-containing channels (homomers and heteromers) is lost upon mutation of a putative phosphorylation site within the intracellular N- and the C-terminal domain of the ASIC1b and ASIC3 subunit, respectively. Moreover, short-term JNK activation regulates the activity of native ASIC1b- and ASIC3-containing channels in rodent sensory neurons and is involved in the rapid potentiation of ASIC activity by the proinflammatory cytokine TNFα. Local JNK activation in vivo in mice induces a short-term potentiation of the acid-induced cutaneous pain in inflammatory conditions that is partially blocked by the ASIC1-specific inhibitor mambalgin-1. Collectively, our data identify pain-related channels as novel physiological JNK substrates in nociceptive neurons, and propose JNK-dependent phosphorylation as a fast post-translational mechanism of regulation of sensory neuron-expressed ASIC1b- and ASIC3-containing channels that may contribute to peripheral sensitization and pain hypersensitivity.

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c-Jun/p38MAPK/ASIC3 pathways specifically activated by nerve growth factor through TrkA are crucial for mechanical allodynia development

Cited by 20 publications

References 55 publications

Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

A proteome signature for acute incisional pain in dorsal root ganglia of mice

C-Jun N-terminal kinase post-translational regulation of pain-related Acid-Sensing Ion Channels 1b and 3

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